HIV-1 and nearly all other lentiviruses encode an accessory protein termed viral infectivity factor (Vif) that is required for productive viral replication and pathogenesis in vivo. Vif functions canonically to overcome restriction by the cellular APOBEC3 (A3) proteins by triggering their polyubiquitination and degradation through an E3 ubiquitin ligase complex. We recently identified the transcription factor CBF as a Vif cofactor required for the assembly and function of this E3 ubiquitin ligase complex. CBF is expressed in CD4+ T cells and functions by heterodimerizing with the DNA binding RUNX transcription factors to regulate expression of genes involved in T cell development and immune function. My preliminary knockdown and knockout experiments indicate that CBF is a positive regulator of A3 transcription in T cells. Ablating CBF function suppresses A3 gene transcription and causes a concomitant increase in Vif-deficient HIV-1 infectivity. I hypothesize that CBF/RUNX complexes directly stimulate A3 gene transcription and that Vif disrupts this process by hijacking CBF to form the Vif/CBF E3 ubiquitin ligase complex that degrades A3 proteins. Thus, Vif efficiently couples two independent and highly complementary mechanisms to suppress A3 antiviral activity. The studies proposed here will test this potentially paradigm-shifting hypothesis, and could provide an elegant evolutionary rationalization for why Vif hijacks CBF as opposed to any other cellular protein.